New arflnoalkylxhioacyipheno-
tfflazines



Y hydrogen or chlorine.

United StatesPatent ()fi ice ilhdfid? Patented June 15,1955

3,189,607 NEW AIVIINOALKYL'I'HIOACYLPHENO- THIAZINES Ernst Habicht andHans Miiller, Schaflhausen, Switzerland, assignors to Cilag-ChemieLimited, Schailihausen, Switzerland, a Swiss company No Drawing. FiledJuly 10, 1962, Ser. No. 208,931

Claims priority, application Switzerland, Aug. 11, 1961,

9,435/ 61 5 Claims. (Cl. 260-243) The present invention relates to neworganic sulfur compounds. In particular the invention relates tosubstances of the general formula EOR1SRgAm (I) wherein R and Rrepresent lower alkylene radicals, Am represents a secondary or tertiaryamino group and R and R represent alkylene radicals which containtogether not more than 6 carbon atoms, Am a lower alkylamino ordialkyla-mino group, a pyrrolidino or piperidino group or aNalkylpiperazino roup.

g The new sulfur compounds and their acid addition salts of the FormulaI have anaesthetic and spasmoly-tic efiect, antiinflammatory elfect,narcosis potentiating effect and temperature lowering efiect, andantagonize the effect of histamine. They can be used to increase theactivity of various pharmaca as analgetics, hypnotics, anaesthetics,spasmolytics. The compounds of the Formula I have'also a psychotropiceffect, particularly as sedative.

Furthermore, the substances of the Formula I have a fungistatic andbacteriostatic effect. The N-quaternary, the N-quaternary and S-ternarysalts respectively have the same efiect, partially intensified.

The new above defined sulfur compounds can be prepared by reacting acompound of the formula do-m-x (n) with a compound of the formula X'RArn the symbols R R and Am having the above cited meaning, while one ofthe symbols X means a reactive splittable radical, as for instancehalogen and the other one represents the thiol group or the thiol groupin salt form. 1

According to this method, a halogenoparafin carboxylic acidphenothiazide, obtained in the usual Way, can be reacted with asecondary or tertiary aminoalkanethio-l or with an alkali metal salt ofsuchan aminoalkanethiol. Instead of a halogenoparaffin carboxylic acidphenothiazide, also an arylor alkyl-sulfonyloxyparaflin carboxylic acidphenothiazide can be used.

A preferential method is to mix a halogenoparaffin carboxylic acidphenothiazide with a secondary or tertiary aminoalkanethiol in a lowerfatty acid nitrile, preferably acetonitrile. The reaction is startedwithout external heating and can be terminated by slightly heating. Whencooling down, the hydrohalogenide of the formedaminoalkylmercapto-parailinoyl phenothiazine crystallizes and can easilybe isolated.

7 According to known manner, it is also possible to react amerca-ptoparatdn carboxylic acid phenothiazide, which is obtained byreaction of a phenothiazine with a thioglycolic acid or a homologthereof, with an aminoalkylhalogen'i'de; thereby working in the presenceof basic condensing agents, for instance alkali metal alcoholates inalcohols.

As already mentioned, the preferential method is the reaction ofhalogenoacyl-phenothiazides with secondary or tertiary aminoakancthiolsin an aliphatic nitrile, preferably acetonitrile, thereby directlyobtaining the hydrohalides of the end products.

There can, for instance, 'be'reacted: 10-chloroacetylphenothiazine,lO-u-chloropropionyl-phenothiazine, 10-,8- bromopropionyl phenothiazine,IO-y-bmmobutymylphenothiazine or the corresponding 3-.chloroderivativeswith dimethylamino ethanethiol, diethylamino ethanethiol,di-n-propylamino-ethanethiol, diisopropyl-aminoethanethiol,di-n-butylamino ethanethiol, pyrrolidino thanethiol,piperidino-ethanethiol, and the corresponding propaneth-iols, forinstance 8-dimet-hylaminopropanethiol, -dimethylamino-propanethiol, asWell as the secondary amino-ethanethiols, such as for instanceethylarninoethanethiol, propylamino-ethanethiol, butylaminoethanethiol.

Instead of the 10-chloroacetyl-phenothiazines, also thea-halogenoprcpionyl or the B-halogenopropionyl compounds can be used asmentioned previously.

The sulfur compounds thus formed of the formula mentioned above can orshall preferably be isolated in form of their salts Oif non-toxicinorganic or organic acids.

The inorganic acids used for the salt formation are: sulfuric acid,hydrochloric acid, hydrobromic acid, phosphoric acids; as organic acidsare used: acetic acid,

'glycolic acid, citric acid, succinic acid, fumaric acid,

maleic acid, dioxymaleic acid, methanesulfonic acid,

acid.

The sulfur compounds thus obtained can also be transformed into theirN-quaternary, N-quaternary and S-ternary salts respectively.

'When working with molar quantities of quaternizing agent, there arepreferably obtained the N-quater-nary salts. If working with excess ofquaternizing agent, then the N-quaternary and S-ternary salts areobtained. As quaternizing agents are used: hydrohalide esters ofaliphatic and araliphatic alcohols, for instance alkylhalo genides,lienylhalogenides, arallrylhalogenides. Instead of halogenides ofalcohols, it is also possible to use the alkanesulfonic acid estersthereof. We prefer lower alkyl ammonium and sulfonium chlorides,bromides and sulrates The quaternization can be carried out in asolvent, for instance in ethylacetate, ether, dioxane.

Example I 60 g. of phenot'uiazine are transferred in the usual way inthe lfl-chloroacetyl compound'by means of 54 g. of chloroacetyl chloride[cf. Acta Chem. Scand. 3, pp. 302- 303 (1949)]. 20 g. of thechloroacetyl compound thus obtained are dissolved in c. of hot redest.acetonitrile. The solution is cooled and 8 g. ofdimethylaminoethanethiol are added. The reaction starts underself-heating. The whole is held for 15 minutes at 45 C. under"turbinating and is then cooled to 10 C. After a few hours, thehydrochloride of the formed l0[(fl-dirnethylamino-etfuylthio)-acetyl]-phenothiazine is sucked ed and Washed with ether. There are obtained 24g. of hydrochloride, melting at l84-i85 C. The base can be freed fromthe jrecrystallize'd from isopropanol.

hydrochloride by means base: 6567C. V

" V Example 2' V 7 or V V 'In thesarne manner as described in Example 1there 7 are obtained'from 20 g. of l flchloroacetyl-phenothiazine and 10'g. of diethylarninoethanethiol 2 5 'g. of hydrochloride of the10-[(fi-diethylaminoethyl thio)-acetyl]-pheno thiazine, melting at189-191 C. The base can be freed by rneans'of alkalies and melts .at6l62 7C. Example 3 In the same manner as'described in Example 1 thereare obtained from 19.3 g. of 1Q-chloroacetyl-phenothia- V zine and 10.7-g. dffpiperidinoethanethiol 26 g. oflO-[flipiperidinoethylthio)-acetyl]phienothiaiine, melting -at' 7679 C.

and melts at 176- 177 C. e

I i. j i ex mpl 4. W V V i From 19.3 g. ofl-chloroacetyl-phenothiazineand 9.65

g. of pyrrolidinoethanethiol in 50 cc. of acetonitrile there is obtainedthe 10-[(fi-pyrrolidinoethylthio)-acetyl] phenothiazine (26 g.) which'metls at 90-91" C. The hydrochloridev of the base melts at 136-137 C.;it can be 7 Example 5 r 7 18.6. g. ofIO-chloroacetyl-Z-chloro-phenothiazine are reacted in the usual mannerWith/.2 g. of piperidinoehhanethiol. There are obtained 22.9 g. of'lO-EQB-pi eridinoethylthio)-acetyl]- 3 -chlorophenothia zine, recrystallizing. frompetroleum ether, and melting'at 81-82 C. The hydrochloridemelts, recrystallized 'form ether/isopropanol, at 176478 C. i

Example 6 7' of alkalies; melting point of the 16-;(fi'-piperidino-ethyl-thio epropionyl-phenothiazine' ltl-B-(fi'-dimethylamino-ethyl-thio -propiony1- phenothiazine V V o 7l0-[3-(,8'-diethylamino ethyl thio-propionyl phenothiazine 1 0-}9-([3'-di-N-propylamirio-ethylfthio propiony le phenothiazine V L f a w 7l958-(fi'rpyrrolidino-ethyl thio)-propionyl-phenothiazine 10-,8-(fi-piperidino-ethyl-thio -propionyl-phent5thiazine What We claim is:

1. A' chemical compound selected from the group consis'ti'ng ofphenothiazine derivatives having the formula: 7

7 From the base there is prepared in acetone 7 V the hydrochloride,which crystallizes from isopropanol V V V N V V V oo-R1s-R1-Am, V V r Vr V wherein R and R represent loweralkylene raclicals which togethercontain not more than 16 "Carb0n atoms; Am is selected'from the groupconsisting of mono-lower:

' alkylamiuo, di-lower alkylarnino, pyrrolidino, piperidino and N-loweralkyl-piperazino and Y is selected from the group consisting of hydro}gen and'c hlorine atoms; and the pharmaceticallyaccept- Front 2117 g. ofV 10r chloroacetyl-3-chloro-phenothia- 'zine and 7.7 g. ofdimethylaminoethanethiol there are obtained 20.4 g. of 10-[fi-dimethylaminoethylthio acetyl]-3-chlorophenothiazine., The basecanleasily be recrystallized from petroleum ether and melts, thuspurified, at a temperature of 76-78 C. :The hydrolchloride melts at194-195 C; it can be recrystallized from isopropanol. e 7

Example 7 7 1 From 21.7g. of10 ch1oroacetyl 3-chloro-phenothiazine and9.8 g; of diethylamino-ethanethiol there are obtained 29 of 10-[,8diethylarninoethylthio-acetyl] -3-enlorophenothiazine. Afterrecrystallization froni petroleuin ether the base melts at 69-72" C. Thehydrochloride prepared with the aid of ethereal hydrochloric acid meltsat 99 C, Afer recrystallization fromisopropanol/ ether, 7 thehydrochloride melts at.l0l103 C.

. As described in th prepared:

.thiazine w-(6' 'zin e 7 V 10-02- (fi' -diethylamine-ethyl-thio)pr'opionyl-phenothia zine 7 imethylamine-ethyl-thio -propiohyl-phenothia- V 7 10-;-(H-pyrrolidinO-ethyl-thio)-propionyl-phenothiazine e'examples therecan further. be I 7 1 Ora- 3- l-rnethyl-piperaiihyl-kethyl-thio-acetyl-phenoacetyH-phenothiazine. r o

5. The compoundz. 1Q-[(,e-pyrrolidinoethylthio) -acetyl]-phenothiazine;7

V V References Cited by the Examiner UNlTED STATES PATENTS.

2,951,077' 8/60 Myers et a1. 260 -243. 2,939,529 6/61 Schuler' 260 243"7 3,074,939 1/63 Davis -7 26 V 7 2 4 3 7 OTHER REFERENCES 7 Lowy et al.:An lnt rodu ctionfto Organic Chemistry} 6th edition, page 213, JohnWiley and Sons (copyright 1945 e V 7 f 'I RVING'MARCU S, Primaryhxqminer. V. 1

ICHOLAS S. RIZZO, WALTER A. MODANCE, V I e V Examiners.

1. A CHEMICAL COMPOUND SELECTED FROM THE GROUP CONSISTING OFPHENOTHIAZINE DERIVATIVES HAVING THE FORMULA: